An overreacting immune system is partly responsible for numerous chronic inflammatory disorders such as, for example, rheumatoid arthritis, Crohn's disease, asthma and multiple sclerosis. An increased release of proinflammatory cytokines leads to damage to endogenous tissue structures. The interplay of the innate and adaptive immune system is of central importance in this connection (Akira et al., 2001). Modulation of the immune system with substances which interfere with the activation of cells of the innate and/or of the adaptive immune system has antiinflammatory effects and can thus alleviate the pathological phenotype in the above disorders mentioned by way of example.
Innate immunity is based on the fact that microorganisms such as bacteria and viruses have certain inherent features via which they are recognized by the immune system and subsequently activate the latter. Certain pathogen-associated patterns (“pathogen associated molecular pattern, PAMPS”) are recognized. PAMPs are recognized by the pattern recognition receptors (PRR), which include Toll-like receptors (TLR) (Janeway and Medzhitov, 2002). TLRs are homologues of the drosophila receptor protein “toll”. There are ten different human TLRs. TLR one and six are coreceptors for TLR2. TLR2 recognizes inter alia lipoproteins and lipopeptides. TLR3 recognizes double-stranded RNA. TLR4 recognizes inter alia LPS of gram-negative and lipoteichoic acid of gram-positive bacteria. TLR5 recognizes flagellin, TLR9 recognizes CpG motifs in bacterial DNA (O'Neill, 2006). Coreceptors may further alter the recognition abilities of TLRs (Jiang et al., 2005).
IL-1/-18, TLR Signal Transduction
TLRs are used in signal transduction with IL-1/IL-18 cytokine receptors. IL-1 (endogenous pyrogen) greatly stimulates inflammation and induces fever. Members of the IL-1R/TLR superfamily have a TIR domain (Toll/IL1 receptor). The TIR domain is about 200 amino acids long and comprises three conserved sequence motifs. Proteins having TIR domains bind via a protein-protein interaction (O'Neill et al., 2005). Subclass one (IL-1R family) comprises three Ig-like domains, and the receptor is a heterodimer. Included therein are IL-1 receptors one and two, the coreceptor IL-1RAcP and the corresponding proteins of the IL-18 system. Subclass two (TLR family) comprises leucine-rich motifs. Toll-like receptors form homo- or heterodimers.
Activation of the TLR or IL-1, -18 receptors by the appropriate ligands initiates a multistage signal cascade. The TLR or IL-1/-18 receptor complex interacts via TIR/TIR contacts with the adaptor protein MyD88. The IL-1 associated receptor kinase (IRAK-1) normally has Tollip (Toll interacting protein) bound, which probably acts as an attenuating molecule (“silencer”). IRAK/Tollip binds to the active TLR/IL-1R complex. MyD88 displaces Tollip, thus activating IRAK1 and IRAK-4, most probably as dimer by transphosphorylation. Active IRAK leaves the receptor and binds in the cytoplasm to the adaptor molecule TRAF (Barton and Medzhitov, 2003). Further proteins are ubiquitinylated via TRAF. Ub-TRAF leads, by an unknown mechanism, to autophosphorylation of the S/T kinase TAK1 (an MAP kinase kinasekinase). TAK1 phosphorylates IκB (NF-κB activation) and MKK6. The latter is responsible for activating the MAP kinases p38 and JNK. NF-κB has been identified as nuclear factor for expression of the light antibody chain kappa in B cells, but is likewise involved in regulating many other genes. NF-κB is retained in the inactive state in the cytoplasm, where it is bound to the inhibitor IκB (Deng et al., 2000). Phosphorylation of IκB leads to proteolytic degradation of the inhibitor IκB, and the transcription factor is able to migrate into the nucleus. NF-κB is a heterodimer composed of the subunits p65 (Rel) and p50 (Bäuerle and Henkel, 1994). There are several members of this family which are able to interact in various ways. NF-κB alone cannot induce transcription. Transcriptional coactivators are necessary for gene activation, such as, for instance, p300 or CBT (Akira and Takeda, 2004).
Activation of receptors containing TIR domains is followed inter alia by release of inflammatory cytokines such as, for example, IL-1, IL-6, IL-23 and TNF-alpha (Adachi et al., 1998).
The structures of the following patent applications form the structurally close prior art:
WO2007/016292 describes N-aryl-2-arylthiazole-4-carboxamide derivatives as biofilm modulators (modulators of bacterial films) which differ because of the bicyclic C-D ring system from the compounds claimed herein. WO2007/035478 discloses compounds which have a carboxyl group in the ortho position instead of a carboxamide group.
U.S. Pat. No. 6,274,738 describes N-aryl-2-pyridylthiazole-4-carboxamide derivatives as compounds which modulate DNA primase. However, these compounds cannot have an aminocarbonyl group on the N-aryl group in the ortho position relative to the pyridylthiazole-4-carboxamide unit. In addition, U.S. Pat. No. 4,879,295 discloses N-tetrazolylthiazolecarboxamides. Thiazolamide derivatives are mentioned in WO2006/122011 as inhibitors of viral replication. WO2005/048953 describes thiazolamide derivatives linked to an isoxazole unit as kinase inhibitors. The structures differ from the structures of the present invention, however.
The compounds disclosed in WO2007/052882 also do not have an aminocarbonyl group in the ortho position relative to the aminocarbonyl-thiazole group. A particular feature of the compounds described in WO2004072025 is, in contrast to the structures disclosed herein, a pyrrolidine ring which is additionally linked to a further substituent (such as, for example, a dimethylamino group) via a nitrogen atom.
WO200512256, WO200677424, WO2006077425 and WO200677428 disclose pyrazole derivatives as kinase inhibitors. Among the structures described are some in which a thiazolamide is linked to the pyrazole unit, although none of the pyrazole nitrogen atoms is in methylated form, and the pyrazole unit is not substituted by an aminocarbonyl group (C(O)NH2) either.
Pyrazolamides which are, however, simultaneously linked to a urea unit are described in WO2005/37797.
WO2005/115986 claims pyridinamides, but in this case no linkages to sulphur-containing heterocycles such as thiazole are envisaged.
Structurally different from the compounds described herein are also the pyridinamides described in WO2005/049604 because of the linkage to an oxygen-substituted phenyl ring.
EP1666455 describes amides with an additional carboxamide structure, it not being possible for the substituent R1 to be an aminocarbonyl group.
Starting from this prior art, the object of the present invention is to provide further structures for therapy, in particular for immunomodulation.
The object is achieved by compounds of the general formula (I) with building blocks A, B, C and D,
in whichthe building blocks B and D are in ortho position relative to one another, and    Q1 is a phenyl ring or hydrogenated bicyclic heteroaryl ring,    R1 and R2 are independently of one another            (i) hydrogen, hydroxy, nitro, halogen, cyano, —CF3, —NR5R6 or        (ii) —O—SO2—NR5R6, —SO2—R7, —SO2—NR5R6,        (iii) —C(O)—OR10, —C(O)—R7, —C(O)—C1-C3-fluoroalkyl, —C(O)—NR5R6, —NH—C(O)—R7 or        (iv) a C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C1-C6-fluoroalkyl or a C1-C6-fluoroalkoxy radical, or        (v) a C1-C6-alkyl radical if Q1 is a hydrogenated bicyclic heteroaryl ring,        where (iv) and/or (v) may optionally be substituted one or more times, identically or differently, by —C1-C3-alkoxy, hydroxy, —C(O)—OR10 or —NR8R9, and            Q2 is an aryl, heteroaryl or a hydrogenated bicyclic heteroaryl ring; and    R3 and R4 are independently of one another            (i) hydrogen, halogen or —NR11R12, or        (ii) a C1-C6-alkyl or C1-C6-alkoxy radical which are in each case optionally substituted one or more times, identically or differently, by hydroxy, C1-C3-alkoxy, —NR8R9 or heterocyclyl, where the heterocyclyl ring may be substituted one or more times, identically or differently, by C1-C3-alkyl or —C(O)—R7, and            R5 and R6 are independently of one another hydrogen or a C1-C6-alkyl radical which is optionally substituted one or more times, identically or differently, by hydroxy, —C1-C3-alkoxy, —NR8R9 or heterocyclyl, where the heterocyclyl ring may be substituted one or more times, identically or differently, by C1-C3-alkyl or —C(O)—R7, or    R5 and R6 form alternatively together with the nitrogen atom a 5- to 7-membered ring which optionally comprises a further heteroatom in addition to the nitrogen atom, and which is optionally substituted one or more times, identically or differently, by C1-C6-alkyl and/or by —C(O)—R7, and    R7 is a C1-C6-alkyl radical, and    R8, R9, R10 are independently of one another hydrogen or a C1-C6-alkyl radical, and    R11 and R12 are independently of one another hydrogen or a C1-C6-alkyl radical which is optionally substituted one or more times, identically or differently, by hydroxy, —C1-C3-alkoxy, —NR8R9 or heterocyclyl, where the heterocyclyl ring may be substituted one or more times, identically or differently, by C1-C3-alkyl or —C(O)—R7,and the salts, enantiomers and diastereomers thereof.
The invention is based on the following definitions:
Cn-Alkyl:
Monovalent, straight-chain or branched, saturated hydrocarbon radical having n carbon atoms.
A C1-C6-alkyl radical includes inter alia for example:
methyl-, ethyl-, propyl-, butyl-, pentyl-, hexyl-, iso-propyl-, iso-butyl-, sec-butyl-, tert-butyl-, iso-pentyl-, 2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-, 1,2-dimethylpropyl-, neo-pentyl-, 1,1-dimethylpropyl-, 4-methylpentyl-, 3-methylpentyl-, 2-methylpentyl-, 1-methylpentyl-, 2-ethylbutyl-, 1-ethyl-butyl-, 3,3-dimethylbutyl-, 2,2-dimethylbutyl-, 1,1-dimethylbutyl-, 2,3-dimethylbutyl-, 1,3-dimethylbutyl-1,2-dimethylbutyl-.
A methyl, ethyl, propyl or isopropyl radical is preferred.
Cn-Fluoroalkyl:
Monovalent, straight-chain or branched, saturated, completely or partly fluorinated, hydrocarbon radical having n carbon atoms.
A C1-C6-fluoroalkyl radical includes inter alia for example:
trifluoromethyl, difluoromethyl, monofluoromethyl, pentafluoroethyl, hepta-fluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 5,5,6,6,6-pentafluoro-hexyl, pentafluoroallyl, 1,1,1,3,3,3-hexafluoro-2-propyl
A trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl radical is preferred.
Cn-Alkenyl:
monovalent, straight-chain or branched hydrocarbon radical having n carbon atoms and at least one double bond.
A C2-C6 alkenyl radical includes inter alia for example:
vinyl-, allyl-, (E)-2-methylvinyl-, (Z)-2-methylvinyl-, homoallyl-, (E)-but-2-enyl-, (Z)-but-2-enyl-, (E)-but-1-enyl-, (Z)-but-1-enyl-, pent-4-enyl-, (E)-pent-3-enyl-, (Z)-pent-3-enyl-, (E)-pent-2-enyl-, (Z)-pent-2-enyl-, (E)-pent-1-enyl-, (Z)-pent-1-enyl-, hex-5-enyl-, (E)-hex-4-enyl-, (Z)-hex-4-enyl-, (E)-hex-3-enyl-, (Z)-hex-3-enyl-, (E)-hex-2-enyl-, (Z)-hex-2-enyl-, (E)-hex-1-enyl-, (Z)-hex-1-enyl, isopropenyl-, 2-methylprop-2-enyl-, 1-methylprop-2-enyl-, 2-methylprop-1-enyl-, (E)-1-methylprop-1-enyl-, (Z)-1-methylprop-1-enyl-, 3-methylbut-3-enyl-, 2-methylbut-3-enyl-, 1-methylbut-3-enyl, 3-methylbut-2-enyl-, (E)-2-methylbut-2-enyl-, (Z)-2-methylbut-2-enyl-, (E)-1-methylbut-2-enyl-, (Z)-1-methylbut-2-enyl-, (E)-3-methylbut-1-enyl-, (Z)-3-methylbut-1-enyl-, (E)-2-methylbut-1-enyl-, (Z)-2-methylbut-1-enyl-, (E)-1-methylbut-1-enyl-, (Z)-1-methylbut-1-enyl-, 1,1-dimethylprop-2-enyl-, 1-ethylprop-1-enyl-, 1-propylvinyl-, 1-isopropyl-vinyl-, 4-methylpent-4-enyl-, 3-methylpent-4-enyl-, 2-methylpent-4-enyl-, 1-methylpent-4-enyl-, 4-methylpent-3-enyl-, (E)-3-methylpent-3-enyl-, (Z)-3-methylpent-3-enyl-, (E)-2-methylpent-3-enyl-, (Z)-2-methylpent-3-enyl-, (E)-1-methylpent-3-enyl-, (Z)-1-methylpent-3-enyl-, (E)-4-methylpent-2-enyl-, (Z)-4-methylpent-2-enyl-, (E)-3-methylpent-2-enyl-, (Z)-3-methylpent-2-enyl-, (E)-2-methylpent-2-enyl-, (Z)-2-methylpent-2-enyl-, (E)-1-methyl-pent-2-enyl-, (Z)-1-methylpent-2-enyl-, (E)-4-methylpent-1-enyl-, (Z)-4-methylpent-1-enyl-, (E)-3-methylpent-1-enyl-, (Z)-3-methylpent-1-enyl-, (E)-2-methylpent-1-enyl-, (Z)-2-methylpent-1-enyl-, (E)-1-methylpent-1-enyl-, (Z)-1-methylpent-1-enyl-, 3-ethylbut-3-enyl-, 3-ethylbut-3-enyl-, 1-ethylbut-3-enyl-, (E)-3-ethylbut-2-enyl-, (Z)-3-ethylbut-2-enyl-, (E)-2-ethylbut-2-enyl-, (Z)-2-ethylbut-2-enyl-, (E)-1-ethylbut-2-enyl-, (Z)-1-ethyl-but-2-enyl-, (E)-3-ethylbut-1-enyl-, (Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl-, (E)-1-ethylbut-1-enyl-, (Z)-1-ethylbut-1-enyl-, 2-propylprop-2-enyl-, 1-propylprop-2-enyl-, 2-isopropylprop-2-enyl-, 1-isopropylprop-2-enyl-, (E)-2-propylprop-1-enyl-, (Z)-2-propylprop-1-enyl-, (E)-1-propylprop-1-enyl-, (Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl-, (Z)-2-isopropylprop-1-enyl-, (E)-1-isopropylprop-1-enyl-, (Z)-1-isopropylprop-1-enyl-, (E)-3,3-dimethylprop-1-enyl-, (Z)-3,3-dimethylprop-1-enyl-, 1-(1,1-dimethylethyl)-ethenyl.
A vinyl or allyl radical is preferred.
Cn-Alkynyl:
Monovalent, straight-chain or branched hydrocarbon radical having n carbon atoms and at least one triple bond.
A C2-C6 alkynyl radical includes inter alia for example:
ethynyl-, prop-1-ynyl-, prop-2-ynyl-, but-1-ynyl-, but-2-ynyl-, but-3-ynyl-, pent-1-ynyl-, prop-2-ynyl-, pent-3-ynyl-, pent-4-ynyl-, hexyl-1-ynyl-, hex-2-ynyl-, hex-3-ynyl-, hex-4-ynyl-, hex-5-ynyl-, 1-methylprop-2-ynyl-, 2-methylbut-3-ynyl-, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl-, 3-methylbut-1-ynyl-, 1-ethylprop-2-ynyl-, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methyl-pent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl-, 1-ethylbut-3-ynyl-, 1-ethylbut-2-ynyl-, 1-propylprop-2-ynyl-, 1-isopropylprop-2-ynyl-, 2,2-dimethylbut-3-ynyl-, 1,1-dimethylbut-3-ynyl-, 1,1-dimethylbut-2-ynyl- or a 3,3-dimethylbut-1-ynyl-.
An ethynyl, prop-1-ynyl or prop-2-ynyl radical is preferred.
Cn-Cycloalkyl:
Monovalent, cyclic hydrocarbon ring having n carbon atoms.
C3-C7-Cycloalkyl ring includes:
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and cycloheptyl.
A cyclopropyl, cyclobutyl, cyclopentyl or a cyclohexyl ring is preferred.
Cn-Alkoxy:
Straight-chain or branched Cn-alkyl ether residue of the formula —OR with R=alkyl.
Cn-Fluoroalkoxy:
Straight-chain or branched Cn-fluoroalkyl ether residue of the formula —OR with R═Cn-fluoroalkyl.
Cn-Aryl
Cn-Aryl is a monovalent, aromatic ring system without heteroatom having n hydrocarbon atoms.
C6-Aryl is phenyl. C1-10-Aryl is naphthyl.
Phenyl is preferred.
Heteroatoms
Heteroatoms mean oxygen, nitrogen or sulphur atoms.
Heteroaryl
Heteroaryl is a monovalent, aromatic ring system having at least one heteroatom different from a carbon. Heteroatoms which may be present are nitrogen atoms, oxygen atoms and/or sulphur atoms. The valence bonds may be on any aromatic carbon atom or on a nitrogen atom.
A monocyclic heteroaryl ring according to the present invention has 5 or 6 ring atoms.
Heteroaryl rings having 5 ring atoms include for example the rings: thienyl, thiazolyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl and thiadiazolyl.
Heteroaryl rings having 6 ring atoms include for example the rings: pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
A bicyclic heteroaryl ring according to the present invention has 9 to 10 ring atoms.
Heteroaryl rings having 9 ring atoms include for example the rings: indolyl, isoindolyl, indazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, azocinyl, indolizinyl, purinyl.
Heteroaryl rings having 10 ring atoms include for example the rings: isoquinolinyl, quinolinyl, cinnolinyl, quinazolinyl, quioxalinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, pteridinyl.
Monocyclic heteroaryl rings having 5 or 6 ring atoms are preferred.
Hydrogenated bicyclic aryl or heteroaryl rings are bicyclic compounds in which one ring is in partly or completely hydrogenated form. The valence bond may be on any atom of the aromatic part of the hydrogenated bicyclic aryl or heteroaryl ring.
Hydrogenated bicyclic aryl or heteroaryl rings include for example the rings: indanyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-1H-isoindolyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 4,5,6,7-tetrahydrothieno-[3,2-c]pyridinyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl, chromanyl, 1,2,3,4-tetrahydroquinoxalinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl.
Hydrogenated bicyclic aryl or heteroaryl rings in which one ring is in partly or completely hydrogenated form may optionally comprise one or two carbonyl groups in the ring system.
Examples thereof are indolonyl, isoindolonyl, benzoxazinonyl, phthalazinonyl, quinolonyl, isoquinolonyl, phthalidyl, thiophthalidyl.
Heterocyclyl
Heterocyclyl in the context of the invention is a completely hydrogenated heteroaryl (completed hydrogenated heteroaryl=saturated heterocyclyl), i.e. a nonaromatic ring system having at least one heteroatom different from a carbon. Heteroatoms which may occur are nitrogen atoms, oxygen atoms and/or sulphur atoms. The valence bond may be on any carbon atom or on a nitrogen atom.
Heterocyclyl ring having 3 ring atoms includes for example:
aziridinyl.
Heterocyclyl ring having 4 ring atoms includes for example:
azetidinyl, oxetanyl.
Heterocyclyl rings having 5 ring atoms include for example the rings:
pyrrolidinyl, imidazolidinyl, pyrazolidinyl and tetrahydrofuranyl.
Heterocyclyl rings having 6 ring atoms include for example the rings:
piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl and thiomorpholinyl
Heterocyclyl rings having 7 ring atoms include for example the rings:
azepanyl, oxepanyl, [1,3]-diazepanyl, [1,4]-diazepanyl.
Heterocyclyl rings having 8 ring atoms include for example:
oxocanyl, azocanyl.
Heterocyclyl rings may optionally be partly unsaturated and/or also comprise a carbonyl group in the ring.
Examples thereof are dihydrofuran-2-onyl, pyrrolidin-2-onyl, piperazin-2-onyl, morpholin-2-onyl, 3(2H)-pyridazinonyl, 5,6-dihydro-2-pyran-2-onyl, 5,6-dihydropyridin-2(1H)-onyl, 2-piperidonyl, 1,2,3,6-tetrahydropyridinyl.
Halogen
The term halogen includes fluorine, chlorine, bromine and iodine.
Likewise to be regarded as encompassed by the present invention are all compounds which result from every possible combination of the abovementioned possible, preferred and particularly preferred meanings of the substituents.
Special embodiments of the invention moreover consist of compounds which result from combination of the meanings disclosed for the substituents directly in the examples.
Likewise to be regarded as encompassed by the present invention are the salts of the compounds.
Formulation of the compounds according to the invention to give pharmaceutical products takes place in a manner known per se by converting the active ingredient(s) with the excipients customary in pharmaceutical technology into the desired administration form.
Excipients which can be employed in this connection are, for example, carrier substances, fillers, disintegrants, binders, humectants, lubricants, absorbents and adsorbents, diluents, solvents, cosolvents, emulsifiers, solubilizers, masking flavours, colorants, preservatives, stabilizers, wetting agents, salts to alter the osmotic pressure or buffers. Reference should be made in this connection to Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).
The pharmaceutical formulations may be
in solid form, for example as tablets, coated tablets, pills, suppositories, capsules, transdermal systems or
in semisolid form, for example as ointments, creams, gels, suppositories, emulsions or
in liquid form, for example as solutions, tinctures, suspensions or emulsions.
Excipients in the context of the invention may be, for example, salts, saccharides (mono-, di-, tri-, oligo-, and/or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils, hydrocarbons and derivatives thereof, where the excipients may be of natural origin or may be obtained by synthesis or partial synthesis.
Suitable for oral or peroral administration are in particular tablets, coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions. Suitable for parenteral administration are in particular suspensions, emulsions and especially solutions.
Owing to their antiinflammatory and additional immunosuppressant effect, the compounds of the invention of the general formula (I) can be used as medicaments for the treatment or prophylaxis of the following pathological states in mammals and humans, for local and systemic administration:    (i) pulmonary disorders associated with inflammatory, allergic and/or proliferative processes:            chronic obstructive pulmonary disorders of any origin, especially bronchial asthma        bronchitis of varying origin        adult respiratory distress syndrome (ARDS), acute respiratory distress syndrome        bronchiectases        all types of restrictive pulmonary disorders, especially allergic alveolitis,        pulmonary oedema, especially allergic        sarcoidoses and granulomatoses, especially Boeck's disease            (ii) rheumatic disorders/autoimmune diseases/joint disorders associated with inflammatory, allergic and/or proliferative processes:            all types of rheumatic disorders, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica, Behcet's disease        reactive arthritis        inflammatory soft tissue disorders of other origin        arthritic symptoms associated with degenerative joint disorders (arthroses)        collagenoses of any origin, e.g. systemic lupus erythematosus,        scleroderma, polymyositis, dermatomyositis, Sjögren's syndrome, Still's syndrome, Felty's syndrome        sarcoidoses and granulomatoses        soft tissue rheumatism            (iii) allergies or pseudoallergic disorders associated with inflammatory and/or proliferative processes:            all types of allergic reactions, e.g. angioedema, hay fever, insect bite, allergic reactions to drugs, blood derivatives, contrast media etc., anaphylactic shock, urticaria, allergic and irritative contact dermatitis, allergic vascular disorders        allergic vasculitis            (iv) vessel inflammations (vasculitides)            panarteritis nodosa, temporal arteritis, erythema nodosum        polyarteritis nodosa        Wegner's granulomatosis        giant cell arteritis            (v) dermatological disorders associated with inflammatory, allergic and/or proliferative processes:            atopic dermatitis (especially in children)        all types of eczema such as, for example, atopic eczema (especially in children)        exanthemas of any origin or dermatoses        psoriasis and parapsoriasis group        pityriasis rubra pilaris        erythematous disorders induced by various noxae, e.g. radiation, chemicals, burns etc.        
bullous dermatoses such as, for example, autoimmune pemphigus vulgaris, bullous pemphigoid                lichenoid disorders        pruritus (e.g. of allergic origin)        rosacea group        erythema exudativum multiforme        manifestation of vascular disorders        hair loss such as alopecia areata        cutaneous lymphomas            (vi) renal disorders associated with inflammatory, allergic and/or proliferative processes:            nephrotic syndrome        all nephritides, e.g. glomerulonephritis            (vii) hepatic disorders associated with inflammatory, allergic and/or proliferative processes:            acute hepatitis of varying origin        chronic aggressive and/or chronic intermittent hepatitis            (viii) gastrointestinal disorders associated with inflammatory, allergic and/or proliferative processes:            regional enteritis (Crohn's disease)        ulcerative colitis        gastroenteritides of other origin, e.g. indigenous sprue            (ix) ocular disorders associated with inflammatory, allergic and/or proliferative processes:            allergic keratitis, uveitis, iritis,        conjunctivitis        blepharitis        optic neuritis        chorioiditis        sympathetic ophthalmia            (x) ear-nose-throat disorders associated with inflammatory, allergic and/or proliferative processes:            allergic rhinitis, hay fever        otitis externa, e.g. caused by contact eczema            (xi) neurological disorders associated with inflammatory, allergic and/or proliferative processes:            cerebral oedema, especially allergic cerebral oedema        multiple sclerosis        acute encephalomyelitis        meningitis, especially allergic        Guillain-Barre syndrome        Alzheimer's disease            (xii) haematological disorders associated with inflammatory, allergic and/or proliferative processes such as, for example, Hodgkin's disease or non-Hodgkin lymphomas, thrombocytaemias, erythrocytoses            acquired haemolytic anaemia        idiopathic thrombocytopenia        idiopathic granulocytopenia            (xiii) neoplastic disorders associated with inflammatory, allergic and/or proliferative processes            acute lymphatic leukaemia        malignant lymphomas        lymphogranulomatoses        lymphosarcomas            (xiv) endocrine disorders associated with inflammatory, allergic and/or proliferative processes such as, for example:            endocrine orbitopathy        de Quervain thyroiditis        Hashimoto thyroiditis        Basedow's disease        granulomatous thyroiditis        lymphadenoid goitre        autoimmune adrenalitis        diabetes mellitus, especially type 1 diabetes        endometriosis            (xv) organ and tissue transplantations, graft-versus-host disease    (xvi) severe states of shock, e.g. anaphylactic shock, systemic inflammatory response syndrome (SIRS)
One aspect of the invention is the use of the compounds according to the invention of the general formula (I) for manufacturing a pharmaceutical.
A further aspect of the invention is the use of the compounds according to the invention for the treatment of disorders associated with inflammatory, allergic and/or proliferative processes.
In the general formula (I), Q1 may be a phenyl ring or hydrogenated bicyclic heteroaryl ring.
Q1 is preferably a phenyl, benzodioxolyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-benzo[1,4]oxazin-7-yl, indanonyl or a 2,3-dihydroindolyl ring.
Q1 is particularly preferably a phenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuranyl or a 3,4-dihydro-2H-benzo[1,4]oxazin-7-yl ring.
In the general formula (I), R1 and R2 may be independently of one another:    (i) hydrogen, hydroxy, nitro, halogen, cyano, —CF3, —NR5R6 or    (ii) —O—SO2—NR5R6, —SO2—R7, —SO2—NR5R6     (iii) C(O)—OR10, —C(O)—R7, —C(O)—C1-C3-fluoroalkyl, —C(O)—NR5R6, —NH—C(O)—R7 or    (iv) a C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C1-C6-fluoroalkyl or a C1-C6-fluoroalkoxy radical, or    (v) a C1-C6-alkyl radical if Q1 is a hydrogenated bicyclic heteroaryl ring, where (iv) and/or (v) may optionally be substituted one or more times, identically or differently, by —C1-C3-alkoxy, hydroxy, —C(O)—OR10 or —NR8R9.
R1 and R2 are preferably independently of one another:    (i) hydrogen, hydroxy, halogen, cyano, —CF3, —NR5R6 or    (ii) —SO2—R7,    (iii) a C1-C6-alkoxy, C1-C6-fluoroalkyl, C1-C6-fluoroalkoxy radical or    (iv) a C1-C6-alkyl radical if Q1 is a hydrogenated bicyclic heteroaryl ring.
R1 and R2 are particularly preferably independently of one another:    (i) hydrogen, halogen, cyano or    (ii) —SO2—R7,    (iii) a C1-C6-alkoxy radical or    (iv) a C1-C6-alkyl radical if Q1 is a hydrogenated bicyclic heteroaryl ring.
In the general formula (I), Q2 may be an aryl, heteroaryl or a hydrogenated bicyclic heteroaryl ring.
Q2 is preferably a:
phenyl, thienyl, thiazolyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-1H-isoindolyl, 4,5,6,7-tetrahydrothieno-[2,3-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, 2,3-dihydrobenzo-furanyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 1,2,3,4-tetrahydroquinoxalinyl or a 3,4-dihydro-2H-benzo[1,4]oxazinyl ring.
Q2 is particularly preferably a phenyl, pyrazolyl or a 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl ring.
In the general formula (I), R3 and R4 may be independently of one another:    (i) hydrogen, halogen or —NR11R12, or    (ii) a C1-C6-alkyl or C1-C6-alkoxy radical which are optionally substituted in each case one or more times, identically or differently, by hydroxy, C1-C3-alkoxy, —NR8R9 or heterocyclyl, where the heterocyclyl ring may be substituted one or more times, identically or differently, by C1-C3-alkyl or —C(O)—R7.
R3 and R4 are preferably independently of one another:    (i) hydrogen, halogen, —NR11R12 or    (ii) a C1-C6-alkyl or C1-C6-alkoxy radical, in each case optionally substituted by morpholine or —NR8R9.
R3 and R4 are particularly preferably independently of one another hydrogen, halogen or C1-C6-alkyl.
In the general formula (I), R5 and R6 can be independently of one another: hydrogen or a C1-C6-alkyl radical which is optionally substituted one or more times, identically or differently, by hydroxy, —C1-C3-alkoxy, —NR8R9 or heterocyclyl, where the heterocyclyl ring may be substituted one or more times, identically or differently, by C1-C3-alkyl or —C(O)—R7,
or
    R5 and R6 form alternatively together with the nitrogen atom a 5- to 7-membered ring which optionally comprises a further heteroatom in addition to the nitrogen atom and which is optionally substituted one or more times, identically or differently, by C1-C6-alkyl and/or by —C(O)—R7.
R5 and R6 are preferably independently of one another hydrogen or a C1-C6-alkyl radical which may optionally be substituted one or more times, identically or differently, by hydroxy, —NR8R9, halogen or C1-C3-alkoxy.
R5 and R6 are particularly preferably independently of one another hydrogen or a C1-C4-alkyl radical.
In the general formula (I), R7 may be a C1-C6-alkyl radical.
R7 is preferably a C1-C4-alkyl radical.
R7 is particularly preferably a C1-C3-alkyl radical.
In the general formula (I), R8, R9, R10 may be independently of one another hydrogen or a C1-C6-alkyl radical.
It is preferred for R8 and R9 to be independently of one another hydrogen or a C1-C4-alkyl radical and for R10 to be hydrogen.
It is particularly preferred for R8 and R9 to be independently of one another hydrogen or a C1-C3-alkyl radical and for R10 to be hydrogen.
In the general formula (I), R11 and R12 may be independently of one another:
hydrogen or a C1-C6-alkyl radical which is optionally substituted one or more times, identically or differently, by hydroxy, —C1-C3-alkoxy, —NR8R9 or heterocyclyl, where the heterocyclyl ring may be substituted one or more times, identically or differently, by C1-C3-alkyl or —C(O)—R7.
R11 and R12 are preferably independently of one another hydrogen or a C1-C6-alkyl radical which may optionally be substituted one or more times, identically or differently, by morpholine or by —N(CH3)2, —NH—CH3 or —NH—C2H5.
R11 and R12 are particularly preferably independently of one another hydrogen or a C1-C6-alkyl radical.
A preferred subgroup is formed by compounds of the formula (I) with building blocks A, B, C and D,
in which the building blocks B and D are in ortho position relative to one another and
    Q1 is a phenyl, benzodioxolyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-benzo[1,4]oxazin-7-yl, indanonyl or a 2,3-dihydroindolyl ring,    R1 and R2 are independently            (i) hydrogen, hydroxy, halogen, cyano, —CF3, —NR5R6 or        (ii) —SO2R7,        (iii) a C1-C6-alkoxy, C1-C6-fluoroalkyl, C1-C6-fluoroalkoxy radical or        (iv) a C1-C6-alkyl radical if Q1 is a hydrogenated bicyclic heteroaryl ring,            Q2 is a phenyl, thienyl, thiazolyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-1H-isoindolyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 1,2,3,4-tetrahydroquinoxalinyl or a 3,4-dihydro-2H-benzo[1,4]oxazinyl ring,    R3 and R4 are independently of one another            (i) hydrogen, halogen, —NR11R12 or        (ii) a C1-C6-alkyl or C1-C6-alkoxy radical,        in each case optionally substituted by morpholine or —NR8R9,        where        R5 and R6 are independently of one another hydrogen or a C1-C6 alkyl radical which may optionally be substituted one or more times, identically or differently, by hydroxy, —NR8R9, halogen or C1-C3-alkoxy, and        R7 is a C1-C4 alkyl radical, and        R8 and R9 are independently of one another hydrogen or a C1-C4 alkyl radical,        R11 and R12 are independently of one another hydrogen or a C1-C6 alkyl radical which may optionally be substituted one or more times, identically or differently, by morpholine or by —N(CH3)2, —NH—CH3 or —NH—C2H5,and the salts, enantiomers and diastereomers thereof.        
Particular preference is given to compounds of the general formula (I) with building blocks A, B, C and D
in which
                the building blocks B and D are in ortho position relative to one another, and        Q1 is a phenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuranyl or a 3,4-dihydro-2H-benzo[1,4]oxazin-7-yl ring, and        R1 and R2 are independently of one another                    (i) hydrogen, halogen, cyano or            (ii) —SO2—R7             (iii) a C1-C6-alkoxy radical or            (iv) a C1-C6-alkyl radical if Q1 is a hydrogenated bicyclic heteroaryl ring, and                        Q2 is a phenyl, pyrazolyl or a 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl ring, and        R3 and R4 are independently of one another hydrogen, halogen or C1-C6-alkyl,        where        R7 is a C1-C3-alkyl radical,        and the salts, enantiomers and diastereomers thereof.Preparation of the Compounds According to the InventionProcess Variant 1:Preparation of the Compounds According to the Invention by Amide Coupling of Final Product        

The compounds according to the invention of the general formula (I) can be prepared by reacting the intermediates of formula (III) with compounds of the formula II through an amide coupling reagent (see Sigma-Aldrich publication Chemfiles, Peptide Synthesis, 2007, 7, No. 2). It is possible in this case to use for example carbodiimides (for example N-cyclohexyl-N′-(2-morpholinoethyl)carbodiimide metho-p-toluenesulphonate CAS2491-17-0) or uronium salts (for example O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU)) in combination with a base such as, for example, pyridine. In this case, Q1, Q2, R1, R2, R3 and R4 have the meanings indicated in the general formula (I) according to claims 1 to 7.
Process Variant 2:

The compounds according to the invention of the general formula (I) are prepared in this variant by reacting the intermediates of formula (IV) with compounds of the formula (II) in the presence of a base such as triethylamine, for example. In this case, Q1, Q2, R1, R2, R3 and R4 have the meanings indicated in the general formula (I) according to claims 1 to 7.
Process Variant 3:
a) Preparation of Intermediates of the Formula (V)

2-Bromothiazole-4-carboxylic acid is reacted with intermediates of the formula (II) through an amide coupling reagent as described in process variant 1 to give intermediates of the formula (V).
b) Preparation of the Final Product

Intermediates of the formula (V) are reacted with boronic acids or boronic acid pinacol esters in a Suzuki-Miyaura reaction to give the compounds according to the invention of the formula (I). Suitable catalysts or ligands in this case are for example the catalysts or catalyst systems described in N. Miyaura, A. Suzuki, Chem. Rev.; 1995; 95(7); 2457-2483 or in C. J. O'Brien et al. Chem. Eur. J. 2006, 12, 4743-4748 and in the Sigma-Aldrich publication Chemfiles, Catalysis 2007, 7, No. 5.
In this case, Q1, Q2, R1, R2, R3 and R4 have the meanings indicated in general formula (I) according to claims 1 to 7.
Purification of the Compounds According to the Invention
In some cases, the compounds according to the invention can be purified by preparative HPLC, for example by an autopurifier apparatus from Waters (detection of the compounds by UV detection and electrospray ionization) in combination with commercially available, prepacked HPLC columns (for example XBridge column (from Waters), C18, 5 μm, 30×100 mm). Acetonitrile/water+0.1% trifluoroacetic acid can be used as solvent system (flow rate 50 ml/min). The HPLC solvent mixture can be removed by freeze-drying or centrifugation. The compounds obtained in this way may be in the form of trifluoroacetic acid (TFA) salts and can be converted into the respective free bases by standard laboratory procedures known to the skilled person. In some cases, the compounds according to the invention can be purified by chromatography on silica gel. In this case for example prepacked silica gel cartridges (for example Isolute® Flash silica gel from Separtis) in combination with a Flashmaster II chromatography apparatus (Argonaut/Biotage) and chromatography solvent or mixtures thereof such as, for example, hexane, ethyl acetate, and dichloromethane and methanol, can be considered.
Structural Analysis of the Compounds According to the Invention:
In some cases, the compounds according to the invention are analysed by LC-MS: retention times Rt from the LC-MS analysis: detection: UV=200-400 nm (Acquity HPLC system from Waters)/MS100-800 daltons; 20 V (Micromass/Waters ZQ 4000) in ESI+ mode (to generate positively charged molecular ions); HPLC column: XBridge (Waters), 2.1×50 mm, BEH 1.7 μm; eluents: A: H20/0.05% HC(O)OH, B: CH3CN/0.05% HC(O)OH. Gradient: 10-90% B in 1.7 min, 90% B for 0.2 min, 98-2% B in 0.6 min; flow rate: 1.3 ml/min. The statement LC-MS (ZQ) refers to the use of a Waters ZQ4000 apparatus and the statement LC-MS (SQD) refers to the use of a Single Quadrupol API (Atomic Pressure Ionization) mass detector (Waters) to record a mass spectrum.